Although synapsins have long been proposed to be key regulators of synaptic vesicle (SV) clustering, their mechanism of action has remained mysterious and somewhat controversial. Here, we review synapsins and their associations with each other and with SVs. We highlight the recent hypothesis that synapsin tetramerization is a mechanism for SV clustering. This hypothesis, which aligns with numerous experimental results, suggests that the larger size of synapsin tetramers, in comparison to dimers, allows tetramers to form optimal bridges between SVs that overcome the repulsive force associated with the negatively charged membrane of SVs and allow synapsins to form a reserve pool of SVs within presynaptic terminals.
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A role for synapsin tetramerization in synaptic vesicle clustering.
J Physiol
July 2024
Temasek Life sciences Laboratory, Singapore.
Although synapsins have long been proposed to be key regulators of synaptic vesicle (SV) clustering, their mechanism of action has remained mysterious and somewhat controversial. Here, we review synapsins and their associations with each other and with SVs. We highlight the recent hypothesis that synapsin tetramerization is a mechanism for SV clustering.
View Article and Find Full Text PDFSynapsin 2a tetramerisation selectively controls the presynaptic nanoscale organisation of reserve synaptic vesicles.
Nat Commun
March 2024
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
Neurotransmitter release relies on the regulated fusion of synaptic vesicles (SVs) that are tightly packed within the presynaptic bouton of neurons. The mechanism by which SVs are clustered at the presynapse, while preserving their ability to dynamically recycle to support neuronal communication, remains unknown. Synapsin 2a (Syn2a) tetramerization has been suggested as a potential clustering mechanism.
View Article and Find Full Text PDFDifferent mechanisms of synapsin-induced vesicle clustering at inhibitory and excitatory synapses.
Cell Rep
August 2023
Neuroscience and Mental Health Program, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore. Electronic address:
Synapsins cluster synaptic vesicles (SVs) to provide a reserve pool (RP) of SVs that maintains synaptic transmission during sustained activity. However, it is unclear how synapsins cluster SVs. Here we show that either liquid-liquid phase separation (LLPS) or tetramerization-dependent cross-linking can cluster SVs, depending on whether a synapse is excitatory or inhibitory.
View Article and Find Full Text PDFTetramerization and ATP binding by a protein comprising the A, B, and C domains of rat synapsin I.
J Biol Chem
March 2004
Howard Hughes Medical Institute and the Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA.
Synapsins are multidomain proteins that are critical for regulating neurotransmitter release in vertebrates. In the present study, two crystal structures of the C domain of rat synapsin I (rSynI-C) in complex with Ca(2+) and ATP reveal that this protein can form a tetramer and that a flexible loop (the "multifunctional loop") contacts bound ATP. Further experiments were carried out on a protein comprising the A, B, and C domains of rat synapsin I (rSynI-ABC).
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